1-45332615-G-T

Position:

• chr1-45332615-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001048174.2(MUTYH):​c.565C>A​(p.Arg189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.34

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.565C>A	p.Arg189Ser	missense_variant	8/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.565C>A	p.Arg189Ser	missense_variant	8/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1153C>A		non_coding_transcript_exon_variant	12/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2021	This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 483935). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 217 of the MUTYH protein (p.Arg217Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This missense variant replaces arginine with serine at codon 217 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2024

The p.R217S variant (also known as c.649C>A), located in coding exon 8 of the MUTYH gene, results from a C to A substitution at nucleotide position 649. The arginine at codon 217 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D;D;D;D;N;D
REVEL	Pathogenic	0.69
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.98, 1.0, 0.99	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.76
MutPred		0.64		.;.;.;.;.;.;.;.;Loss of methylation at R217 (P = 0.0344);.;.;.;
MVP		0.97
MPC		0.56
ClinPred		0.93	D
GERP RS		2.1
Varity_R		0.73
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs537292657; hg19: chr1-45798287;